Vulnerability to alcoholism is influenced by genetic as well as environmental determinants. This important finding has stimulated a search for biochemical, hormonal, physiological, and genetic markers to identify nonalcoholic individuals at increased risk of developing alcoholism. The hypothalamic-pituitary-adrenal (HPA) axis is altered by ethanol exposure. Furthermore, evidence is mounting which shows that the dynamics of the HPA axis may differ markedly in high-risk compared to low-risk nonalcoholic individuals. However, studies of this problem have not been comprehensive nor conclusive. High risk subjects are defined as persons with a history of alcoholism in the biological father and are referred to as family history positive (FHP). Low-risk subjects are defined as persons with no history of alcoholism in first- or second- degree biological relatives and are referred to as family history negative (FHN). In the present proposal, we shall compare dynamics of the HPA axis in FHP and FHN nonalcoholic subjects. First, we will identify potential differences in the pulsatile mode of ACTH and cortisol release. This will be accomplished by measuring hormone concentrations in blood samples collected at 10-min intervals over a 24-h period. We will apply deconvolution analysis to the 24-h time series to specifically define the individual secretion and clearance rates of ACTH and cortisol in both groups. Regulation of the hypothalamus, pituitary and adrenal glands will be studied after administration of CRH, Cortrosyn, naloxone and placebo in order to test: i) the pituitary corticotropic response to exogenously- administered CRH; ii) the adrenal gland's response to endogenously- generated and exogenously-administered ACTH; iii) and the magnitude of centrally activating the HPA stress response following opiate blockade with naloxone. It is important to determine if the HPA axis can serve as a marker to identify nonalcoholic individuals at increased risk for the future development of alcoholism. Markers for a genetic vulnerability toward alcoholism could be used to select high-risk individuals for primary prevention and allow investigations of environmental factors or pharmacological agents that may prevent expression of alcoholism. Markers may be used in longitudinal studies to determine whether the markers are primary (causally related) or secondary (genetically linked to causal factors). The resultant knowledge will aid in the diagnosis, evaluation, management and prognosis of alcoholism.